1. Field of the Invention
The present invention relates generally to devices and methods for treating patients suffering from renal insufficiency and/or hepatic insufficiency. More particularly, the invention relates to devices and methods for performing continuous flow-through peritoneal dialysis.
2. Discussion of Related Technology
Irreversible end-stage kidney disease was recently reported to occur with an annual frequency of about 1 in 5000 to 10,000 in the general population, with this rate increasing. Until the 1960s, such disease was universally fatal. In the last four decades, various interventions have been developed and implemented for preserving life after loss of all or most of a patient""s own kidney function.
The normal function of the mammalian kidney includes such activity as maintaining a constant acid-base and electrolyte balance, removing excess fluids and removing undesirable products of the body""s metabolism from the blood. In an individual with end stage renal disease, this functioning of the kidney may be reduced to as low as 5% or less of the normal level. When renal function has decreased to this point, artificial means must then be employed to substitute for the kidney activity, if life is to be sustained. This is accomplished clinically by the use of dialysis.
One of the most common methods for achieving this is hemodialysis, in which the patient""s blood is moved outside of the patient""s body and passed through an artificial kidney dialysis machine. In the machine, a synthetic non-permeable membrane acts as an artificial kidney with which the patient""s blood is contacted on one side; on the opposite side of the membrane is a dialyzing fluid or dialysate, the composition of which is such that the undesirable products in the patient""s blood will naturally pass across the membrane by diffusion, into the fluid. The blood is thus cleansed, in essentially the same manner as the kidney would have done, and the blood is returned to the patient""s body.
There are, however, a number of disadvantages inherently associated with hemodialysis. For instance, poor peripheral vasculature in some patients makes removal of the patient""s blood for hemodialysis unfeasable. Additionally, extracorporeal handling of blood is inherently dangerous due to the risk of introducing, for example, bacterial or other contaminants or air bubbles into the blood. Further, equipment needed for performing hemodialysis is guide complicated and expensive.
Some of the disadvantages associated with extracorporeal treatment of blood by hemodialysis are overcome by the use of techniques which utilize the patient""s own peritoneum as the required semipermeable membrane. Presently, a great deal of interest is being given to the development of improved methods for removing undesirable products from the blood through the peritoneum, an intricate membrane-like tissue that lines the abdominal cavity and covers the liver, kidneys, intestine and other internal organs. The peritoneum contains large numbers of blood vessels and capillaries and is thus capable of acting as a natural semipermeable membrane. In a peritoneal dialysis procedure, dialysis solution, or xe2x80x9cdialysatexe2x80x9d is introduced into the peritoneal cavity, via a catheter in the abdominal wall, and a suitable period of residence time for the dialysate is typically allowed to permit the exchange of solutes between it and the blood. The waste products removed from the patient""s blood in this manner typically consist of solutes like sodium and chloride ions, and the other compounds normally excreted through the kidneys like urea, creatinine, and water. Fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate to permit water outflow from the blood. The diffusion of water across the peritoneal membrane during dialysis is called ultrafiltration. Conventional peritoneal dialysis solutions include glucose in concentrations sufficient to generate the necessary osmotic pressure to remove water from the patient""s blood. Thus, the proper acid-base, electrolyte and fluid balance is returned to the blood and the dialysis solution is simply drained from the body cavity through the catheter.
Continuous Ambulatory Peritoneal Dialysis (CAPD) is a popular form of peritoneal dialysis (PD). A patient performs CAPD manually about four times a day. During CAPD, the patient drains spent peritoneal dialysis solution from his/her peritoneal cavity. The patient then infuses fresh peritoneal dialysis solution into his/her peritoneal cavity. This drain and fill procedure usually takes about 1 hour.
Automated Peritoneal Dialysis (APD) is another popular form of PD. APD uses a machine, called a cycler, to automatically infuse, dwell, and drain peritoneal dialysis solution to and from the patient""s peritoneal cavity. APD is particularly attractive to a PD patient, because it can be performed at night while the patient is asleep. This frees the patient from the day-to-day demands of CAPD during his/her waking and working hours. The APD sequence typically lasts for several hours. It often begins with an initial drain cycle to empty the peritoneal cavity of spent dialysate. The APD sequence then proceeds through a succession of fill, dwell, and drain phases that follow one after the other. Each fill/dwell/drain sequence is called a cycle.
During the fill phase, the cycler transfers a predetermined volume of fresh, warmed dialysate into the peritoneal cavity of the patient. The dialysate remains (or xe2x80x9cdwellsxe2x80x9d) within the peritoneal cavity for a time. This is called the dwell phase. During the drain phase, the cycler removes the spent dialysate from the peritoneal cavity. The number of fill/dwell/drain cycles that are required during a given APD session depends upon the total volume of dialysate prescribed for the patient""s APD regime.
Continuous Cycling Peritoneal Dialysis (CCPD) is one commonly-used APD modality. During each fill/dwell/drain phase of CCPD, the cycler infuses a prescribed volume of dialysate. After a prescribed dwell period, the cycler completely drains this liquid volume from the patient, leaving the peritoneal cavity empty, or xe2x80x9cdry.xe2x80x9d Typically, CCPD employs 6 fill/dwell/drain cycles to achieve a prescribed therapy volume. After the last prescribed fill/dwell/drain cycle in CCPD, the cycler infuses a final fill volume. The final fill volume dwells in the patient through the day. It is drained at the outset of the next CCPD session in the evening. The final fill volume can contain a different concentration of glucose than the fill volume of the successive CCPD fill/dwell/drain fill cycles the cycler provides.
Intermittent Peritoneal Dialysis (IPD) is another APD modality. IPD is typically used in acute situations, when a patient suddenly enters dialysis therapy. IPD can also be used when a patient requires PD, but cannot undertake the responsibilities of CAPD or otherwise do it at home. Like CCPD, IPD involves a series of fill/dwell/drain cycles. The cycles in IPD are typically closer in time than in CCPD. In addition, unlike CCPD, IPD does not include a final fill phase. In IPD, the patient""s peritoneal cavity is left free of dialysate (or xe2x80x9cdryxe2x80x9d) in between APD therapy sessions.
Tidal Peritoneal Dialysis (TPD) is another APD modality. Like CCPD, TPD includes a series of fill/dwell/drain cycles. Unlike CCPD, TPD does not completely drain dialysate from the peritoneal cavity during each drain phase. Instead, TPD establishes a base volume during the first fill phase and drains only a portion of this volume during the first drain phase. Subsequent fill/dwell/drain cycles infuse then drain a replacement volume on top of the base volume, except for the last drain phase. The last drain phase removes all dialysate from the peritoneal cavity. There is a variation of TPD that includes cycles during which the patient is completely drained and infused with a new fill base volume of dialysis. TPD can include a final fill cycle, like CCPD. Alternatively, TPD can avoid the final fill cycle, like IPD.
While there are a number of peritoneal dialysis techniques available which generally provide a less-intrusive and safer alternative to extracorporeal hemodialysis, methods have not hereinbefore been provided which achieve optimal clearance of toxins from the blood. In an attempt to overcome this problem, an alternative type of PD has been explored, called Continuous Flow-through Peritoneal dialysis (CFPD). A few studies in the past have shown that higher efficiency of chemical transfer in PD can be achieved if fluid is directed through the peritoneum in a unidirectional manner, from the right to left side of the peritoneum. Gordon A, Lewin A J, Maxwell M H, Morales N D. Augmentation of efficiency by continuous flow sorbent regeneration peritoneal dialysis. Trans ASAIO 23: 599-604, 1976; Shinaberger J M, Shear L, Barry K G. Increasing efficiency of peritoneal dialysis. Experience with peritoneal-extracorporeal recirculation dialysis. Trans ASAIO 11: 76, 1965; and Raja R M, Kramer M S, Rosenbaum J L. Recirculation peritoneal dialysis with sorbent REDY cartridge. Trans ASAIO 13:164, 1967. For Example, with 100 ml/min of dialysate flow, creatinine clearances of up to 20 ml/min have been achieved, many times the clearances of CAPD. However, there were disadvantages associated with this type of therapy, and it did not gain acceptance as a suitable alternative to other PD techniques. One disadvantage was that this procedure required two catheters rather than one. Additionally, difficulty has been experienced in achieving continuous outflow at sufficient rates without experiencing blockage of the outflow catheter. As such, there is a need in the art for improved devices and methods for performing CFPD.
Turning now to an additional need for blood purification techniques, the liver is another organ which functions to purify blood. Additionally, the liver performs many additional complex biological functions that are critical for the homeostasis of the human body. Although individual pathways for synthesis and breakdown of carbohydrates, lipids, amino acids, proteins, and nucleic acids can be identified in other mammalian cells, only the liver performs all these biochemical transformations simultaneously and is able to combine them to accomplish its vital biologic task. The liver is also the principal site of biotransformation, activation or inactivation of drugs and synthetic chemicals. Therefore, this organ displays a unique biologic complexity. When it fails, functional replacement presents one of the most difficult challenges in substitutive medicine. Artificial means, such as those used to substitute for kidney activity, are not as direct when replacement of liver function is needed.
Under normal physiologic requirements, the liver modifies the composition and concentration of the incoming nutrients for its own usage and for the benefit of other tissues. Among the major liver functions, the detoxification of foreign toxic substances (xenobiotics), the regulation of essential nutrients, and the secretion of transport proteins and critical plasma components of the blood coagulation system are probably the main elements to evaluate in a successful organ replacement. The liver also synthesizes several other critical proteins, excretes bile, and stores excess products for later usage, functions that can temporarily be dispensed with but must eventually be provided. The challenge of liver support in case of organ failure is apparent from the complexity of functions served by liver cells and from our still imperfect ability to rank these functions in terms of urgency of replacement.
The concept of artificial liver support is predicated on the therapeutic benefit for removing toxic substances accumulating in the circulation of liver failure patients. Technologies for temporary liver support focus on the detoxifying function, since this appears to be the most urgent problem in liver failure. The procedures and devices which have been considered for this purpose include the following:
Hemodialysis
Hemodialysis with conventional cellulosic membranes (cut-off point around 5000 daltons) or more permeable polysulfone or polyacrylonitrile (cut-off around 30,000 daltons) helps to restore electrolyte and acid-base balance and may decrease the blood ammonia levels but cannot remove large molecules and plasma protein-bound toxins. Improvement of the patient""s clinical condition (e.g., amelioration of consciousness and cerebral edema) is temporary. The treatment appears to have no lasting value and no demonstrated effect on patient survival. In addition, hemodialysis may produce a respiratory distress syndrome caused by a complement-mediated poly-morphonuclear cell aggregation in the pulmonary circulatory bed. Because some of the clinical benefit seems related to the removal of toxic molecules, more aggressive approaches focused on detoxification have been attempted.
Hemofiltration
Hemofiltration with high cut-off point membranes (around 50,000 daltons with some poly-acrylonitrile-polyvinyl chloride copolymers, modified cellulose""s, or polysulfones) clears natural or abnormal compounds within limits imposed by convective transport across the exchange membrane. These procedures again have a temporary favorable effect on hepatic encephalopathy (perhaps because of the correction of toxic levels of certain amino acids) with reversal of coma, but they do not clearly improve survival rates.
Hemoperfusion
Hemoperfusion, i.e., extracorporeal circulation of blood over nonspecific sorbents (e.g., activated charcoal) or more complex biochemical reactors which allow the chemical processing of specific biologic products, such as ammonia, have not yet met clinical success in spite of encouraging experimental results, except in the case of hepatic necrosis induced by poisonous mushrooms such as Amanita phalloides. Anion exchange resins and affinity columns similar to those used in separative chromatography may help in removing protein-bound substances (e.g., bilirubin) which would not pass through hemodialysis or hemofiltration membranes, but nonspecific sorbents may also deplete the plasma of biologically important substances. Further, these techniques are complicated by problems of hemocompatibility, related in part to the entertainment of dust (xe2x80x9cfinesxe2x80x9d) associated with the sorbent material itself and in part to platelet activation in patients with an already compromised coagulation status. To minimize this problem, direct blood or plasma contact with the sorbent material can be avoided by polymer coating of the sorbent particles using either albumin, cellulose nitrate, or similar thin films, but hemocompatability remains a concern. Here again, there is anecdotal evidence of clinical improvement of hepatic failure with hemoperfusion, with some reports claiming a higher survival rate in hepatic encephalopathy, but these reports have not been supported by well-controlled studies. As is the case for hemodialysis and hemofiltration, the possible beneficial effect of hemoperfusion should be evaluated in the context of the clinical variability in the course of fulminant hepatic failure.
Plasmapheresis
Plasmapheresis, i.e., the combination of withdrawal of blood, centrifigation, or membrane processing to separate and discard the patient""s plasma, and return of autologous cells diluted with donor plasma, was practiced initially as a batch process. Techniques now exist for a continuous exchange process, in which plasma and cells are separated by physical means outside of the body (membrane separation or centrifugation), and the patient""s plasma replaced by banked plasma (up to 5000 ml per day). There is evidence from controlled clinical trials for the effectiveness of this form of therapy, but the mortality rate remains high in patients with hepatic failure, whether from insufficient treatment or the risks of the procedure. It appears, however, that plasma exchange can be beneficial in the preoperative period prior to liver transplantation so as to correct severe coagulopathy. Plasmapheresis is used in conjunction with the placement of a hepatocyte-seeded extracorporeal hollow-fiber device to treat acute and chronic liver.
Combined Therapy
Endotoxins and cytokines can be removed by hemoperfusion over activated charcoal and adsorbent resins, but it may be more effective to process plasma than whole blood. This has led to the concept of combining plasmapheresis with continuous plasma treatment for removal of substances such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and bile acids by a resin column, and then ultrafiltration or dialysis for fluid removal, since patients with liver failure often develop secondary renal failure.
Hemoperfusion Over Liver Tissue Slices
The incorporation of active hepatocytes in a hemoperfusion circuit was suggested by the laboratory practice of biochemists who have investigated metabolic pathways in tissue slices. For liver replacement, this technology has been pursued primarily in Japan as a substitute for organ transplantation, which is culturally frowned upon in that country, in spite of a major incidence of severe liver disease. The procedure may improve biochemical markers of liver failure but has, to date, failed to demonstrated clinical value.
In view of the insufficiency of the above treatments to satisfactorily treat a patient suffering from hepatic insufficiency, there is a great need in the art for improved devices and methods for treating such a patient. Such devices and methods are provided by the present invention, in which there are provided peritoneal dialysis devices and methods which improve the blood composition of a patient suffering from hepatic insufficiency.
The present invention relates generally to advantageous devices and methods for treating patients suffering from renal insufficiency and/or hepatic insufficiency. More particularly, the invention relates in certain aspects to devices and methods for performing continuous flow-through peritoneal dialysis (CFPD). In another aspect of the invention, a peritoneal dialysis system is provided which utilizes a bioreactor to regenerate peritoneal fluid for re-infusion into a peritoneal cavity. Devices and methods of the present invention utilize in preferred embodiments the advantageous features of a dual lumen catheter, preferably a T-fluted dual lumen catheter, combined with a substantially constant rate of dialysate inflow and a pressure-dependent outflow controller, also referred to herein as a xe2x80x9cpressure regulatorxe2x80x9d or a xe2x80x9cpressure-activated valvexe2x80x9d. The invention, therefore, provides in certain aspects advantageous systems for passing fluid through a patient""s peritoneal cavity at a relatively high flow rate, while maintaining in the peritoneal cavity an optimal dialysate pressure, to thereby alter the contents of the patient""s blood by diffusion of molecules through the peritoneal membrane.
In one aspect of the invention, there is provided a device for performing continuous flow peritoneal dialysis, comprising a dialysate source; a peritoneal fluid receptacle; a flexible catheter having a first segment comprising a conduit which defines a first lumen and a second lumen, and a second segment comprising a first limb which defines a recess in fluid communication with the first lumen and a second limb which comprises a T-fluted configuration defining recesses in fluid communication with the second lumen, the first and second limbs being formed to move independently of one another and having distal ends opposite the first segment; a first tube in fluid communication with the dialysate source and the first lumen; a second tube in fluid communication with the second lumen and the peritoneal fluid receptacle; and a pressure regulator in fluid communication with the second tube for maintaining a pressure within the peritoneal cavity of from about 6 to about 20.
In another aspect of the invention, there is provided a device for performing continuous flow peritoneal dialysis, comprising a dialysate source; peritoneal fluid receptacle; a first catheter in fluid communication with the dialysate source, the first catheter defining a first lumen and comprising a first segment configured to be positioned across a patient""s abdominal wall and a second segment configured to reside in the patient""s peritoneal cavity; a second catheter in fluid communication with the peritoneal fluid receptacle, the second catheter defining a second lumen and comprising a first segment configured to be positioned across a patient""s abdominal wall and a second segment configured to reside in the patient""s peritoneal cavity; a first tube in fluid communication with and positioned between the dialysate source and the first lumen; a second tube in fluid communication with and positioned between the second lumen and the peritoneal fluid receptacle; and a pressure regulator in fluid communication with the second tube for maintaining a pressure within the peritoneal cavity of from about 6 to about 20 mm Hg.
In accordance with another aspect of the invention, there is provided a method for removing toxins from a patient""s blood, comprising passing a dialysate into a patient""s peritoneal cavity through a first lumen of a flexible dual lumen catheter at a substantially continuous rate of from about 20 to about 300 ml/min; and recovering peritoneal fluid from the peritoneal cavity through a second lumen of the catheter, provided that fluid is recovered only when fluid in the peritoneal cavity reaches a pressure of from about 6 to about 20 mm Hg; wherein the catheter has a first segment comprising a conduit which defines a first lumen and a second lumen, and a second segment comprising a first limb which defines one or more recesses in fluid communication with the first lumen and a second limb which defines one or more recesses in fluid communication with the second lumen, the first and second limbs being formed to move independently of one another and having distal ends opposite the first segment.
In accordance with another aspect of the invention, there is provided a method for removing toxins from a patient""s blood, comprising passing a dialysate into a patient""s peritoneal cavity through a first lumen of a first catheter at a substantially continuous rate of from about 20 to about 300 ml/min; and recovering peritoneal fluid from the peritoneal cavity through a second lumen of a second catheter, provided that fluid is recovered only when fluid in the peritoneal cavity reaches a pressure of from about 6 to about 20 mm Hg; wherein the first and second catheters are positioned across the patient""s abdominal wall, thereby providing access to the peritoneal cavity.
In accordance with another aspect of the invention, there is provided a device for performing continuous flow peritoneal dialysis, comprising a fluid container; a flexible catheter having a first segment comprising a conduit which defines a first lumen and a second lumen, and a second segment comprising a first limb which defines a recess in fluid communication with the first lumen and a second limb which comprises a T-fluted configuration defining recesses in fluid communication with the second lumen, the first and second limbs being formed to move independently of one another and having distal ends opposite the first segment; a first tube in fluid communication with the first lumen and in fluid communication with the fluid container; a second tube in fluid communication with the second lumen and in fluid communication with the fluid container; wherein the catheter is configured such that the second segment may be positioned within the peritoneal cavity of a patient such that the distal end of the first limb may be placed anterior to the patient""s liver and the distal end of the second limb may be placed substantially adjacent the patient""s pelvis, thereby forming a closed fluid circuit for passing dialysate through the peritoneal cavity in a substantially unidirectional manner.
In accordance with another aspect of the invention, there is provided a device for performing continuous flow peritoneal dialysis, comprising a fluid container; a first catheter in fluid communication with the fluid container, the first catheter defining a first lumen and comprising a first segment configured to be positioned across a patient""s abdominal wall and a second segment configured to reside in the patient""s peritoneal cavity; a second catheter in fluid communication with the fluid container, the second catheter defining a second lumen and comprising a first segment configured to be positioned across a patient""s abdominal wall and a second segment configured to reside in the patient""s peritoneal cavity; a first tube in fluid communication with and positioned between the container and the first lumen; a second tube in fluid communication with and positioned between the second lumen and the container; and a pressure regulator in fluid communication with the second tube for maintaining a pressure within the peritoneal cavity of from about 6 to about 20 mm Hg.
In accordance with another aspect of the invention, there is provided a method for removing toxins from a patient""s blood, comprising passing a dialysate into a patient""s peritoneal cavity from a fluid container through a first tube and a first lumen of a flexible dual lumen catheter at a substantially continuous rate of from about 20 to about 300 ml/min; and recovering peritoneal fluid from the peritoneal cavity through a second lumen of the catheter, provided that fluid is recovered only when fluid in the peritoneal cavity reaches a pressure of from about 6 to about 20 mm Hg; and passing the peritoneal fluid to the container through a second tube; wherein the catheter has a first segment comprising a conduit which defines a first lumen and a second lumen, and a second segment comprising a first limb which defines one or more recesses in fluid communication with the first lumen and a second limb which defines one or more recesses in fluid communication with the second lumen, the first and second limbs being formed to move independently of one another and having distal ends opposite the first segment.
In accordance with another aspect of the invention, there is provided a device for treating a patient for hepatic insufficiency, comprising a fluid container; a first conduit having a proximal end in fluid communication with the container for passing fluid from the container into a patient""s peritoneal cavity through a distal end of the conduit; a second conduit having a proximal end in fluid communication with the container and a distal end in fluid communication with the peritoneal cavity for moving fluid from the peritoneal cavity to the container; and a bioreactor in fluid communication with the second conduit for conditioning the fluid.
In accordance with another aspect of the invention, there is provided a device for treating a patient for hepatic insufficiency, comprising a fluid container; a first conduit in fluid communication with the container; a second conduit in fluid communication with the container; a catheter having a proximal end, a first lumen and a second lumen, wherein the proximal end of the first lumen is in fluid communication with the first conduit, wherein the proximal end of the second lumen is in fluid communication with the second conduit, and wherein the first and second lumens have distal ends positioned in a patient""s peritoneal cavity such that the first and second lumens are in fluid communication with the peritoneum, thereby providing a closed fluid circuit; means for passing fluid from the container, through the first conduit and first lumen and into the peritoneal cavity; and a bioreactor in fluid communication with the second conduit for conditioning fluid exiting the peritoneal cavity.
In accordance with another aspect of the invention, there is provided a method for treating a patient for hepatic insufficiency, comprising passing a fluid from a fluid container into a patient""s peritoneal cavity at a rate of from about 20 to about 300 ml/min, the fluid selected from the group consisting of fresh dialysate, conditioned peritoneal fluid and mixtures thereof; removing peritoneal fluid from the peritoneal cavity at a rate which maintains a fluid pressure in the peritoneum of from about 6 to about 20 mm Hg; conditioning the peritoneal fluid by contacting the fluid with hepatocytes to provide a conditioned peritoneal fluid; and introducing the conditioned peritoneal fluid into the container.
In accordance with another aspect of the invention, there is provided a method for treating a patient for hepatic insufficiency, comprising providing a device comprising a fluid container, a first conduit having a proximal end in fluid communication with the container for passing fluid from the container into a patient""s peritoneal cavity through a distal end of the conduit, a second conduit having a proximal end in fluid communication with the container for moving fluid from the peritoneal cavity to the container and a bioreactor in fluid communication with the second conduit for conditioning the fluid; placing a distal end of the first conduit and a distal end of the second conduit into the peritoneal cavity, thereby providing a closed fluid circuit; and passing fluid through the circuit, maintaining a fluid pressure within the peritoneal cavity of from about 6 to about 20 mm Hg.
It is an object of the present invention to provide improved methods of performing peritoneal dialysis for treating patients suffering from renal and/or hepatic insufficiency.
Further objects, advantages and features of the present invention will be apparent from the detailed description herein.